I recently received a thoughtful message from Shruti, a caregiver member of our community, who has been researching the latest treatments for IDH1-mutated intrahepatic cholangiocarcinoma. She had some important questions about PARP inhibitors and ongoing clinical trials, which could be relevant for patients here in Australia. I try to keep these messages as close to verbatim as possible to maintain their authenticity and personal meaning—because cancer is deeply personal, and sharing is a powerful part of the process.

I really appreciate Shruti reaching out to me with these thoughtful questions—her message will not only help her but also many others in our community who may be seeking similar insights. It’s these kinds of conversations that create a ripple effect, allowing us to share information that can benefit a wider audience.

Here’s what she wrote:

Shruti’s Message:

“Hi Steve, I hope you and Claire are doing well. I’ve been doing some research and came across an article mentioning a PARP inhibitor being tested for IDH1-mutated intrahepatic cholangiocarcinoma. I’m curious if you know more about this. I’ve struggled to find updates on whether the trial is still ongoing, its name, or if there’s any information about it coming to Australia soon. Any insight you could provide would be helpful!”
— Shruti

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If this resonates with you, or if you have additional thoughts, questions, or insights to share, feel free to leave a message below this article or reach out to me directly via email. steve@cholangio.org or comment on this article on our Cholangiocarcinoma Australasian Community – Facebook group.

Do you have a Question? 

Message me on Facebook or email me at steve@cholangio.org – “Subject line: I have a Question”

Hi Shruti,

Great to hear from you, and thanks for reaching out! Claire and I are, as usual, really busy—there’s so much to get done to stay ahead of the cholangio cancer curve.

But I think we’re starting to make a real impact through our strategy to empower our community, including caregivers like yourself, to be more constructive in how they approach the challenges of cholangiocarcinoma. Whether it’s for patients or their support networks, our goal is to equip everyone to build effective response strategies, shifting from being a passive participant to taking the lead—just as you’ve done for Shelly.

Every patient and caregiver we work with helps us improve how we can support the entire community in managing these diagnoses. Claire and I believe we’re seeing more and more families doing well, and this reassures us that our efforts are making a real difference. Nothing is more rewarding than that. You’re a key part of this effort, and your dedication gives Claire and me even greater hope—so yes, in that context, we’re doing well. I hope you and Shelly are doing well too.

Regarding the article you mentioned on PARP inhibitors for IDH1-mutated intrahepatic cholangiocarcinoma (iCCA), I’ve had a chance to look into it. It discusses a case series of patients treated with PARP inhibitors (PARPi) at the University of Michigan from 2018 to 2023. While the results showed that PARPi monotherapy had limited benefit, combining PARP inhibitors with other treatments, like immune checkpoint inhibitors (ICIs) or ATR inhibitors, appeared to offer better results. Two patients even had a partial response to the combination therapy.

The video below will help in gaining a better understanding: 

Explanation of Terms:

• PARP: Stands for Poly(ADP-ribose) polymerase, a protein that helps cells repair damaged DNA. PARP inhibitors block this repair mechanism in cancer cells, leading to their death, especially in cancers with faulty DNA repair mechanisms like those with IDH1 mutations.
• IDH1: Isocitrate Dehydrogenase 1 is a gene that usually helps cells produce energy by converting isocitrate to alpha-ketoglutarate (α-KG). However, when mutated, IDH1 creates a toxic byproduct called 2-HG (2-hydroxyglutarate) instead of α-KG. This toxic waste builds up inside the cell, polluting it and disrupting the cell’s normal DNA messaging and repair functions. As a result, more mistakes occur in the DNA, increasing the risk of cancer development. Understanding this can help you see why treatments like PARP inhibitors are particularly effective for cancers with this mutation—they target and block these faulty DNA repair pathways, preventing the cancer from repairing itself and spreading.
• 2-HG: This is the toxic waste product produced by the mutated IDH1 gene.
• iCCA: Intrahepatic Cholangiocarcinoma, a type of bile duct cancer located in the liver.
• ATR inhibitors: ATR stands for Ataxia Telangiectasia and Rad3-related. RAD3 is a protein involved in repairing damaged DNA, helping cells survive when their DNA is damaged. ATR inhibitors are drugs that block this repair process, making it harder for cancer cells to fix their damaged DNA. When used together with PARP inhibitors (which also stop DNA repair), the combination attacks the cancer cells’ ability to survive by stopping them from fixing their broken DNA. This approach can make the treatment more effective, especially in cancers that depend on these repair systems to grow.
• ICIs (Immune Checkpoint Inhibitors): Drugs that boost the immune system’s ability to recognise and destroy cancer cells. They are sometimes used with PARP inhibitors to enhance treatment effectiveness.
• PFS (Progression-Free Survival): How long a patient’s cancer stays stable (doesn’t get worse) after treatment.
• OS (Overall Survival): The total time a patient survives after treatment.

Current Clinical Trials:

There are still ongoing trials exploring these combinations, including:

1. NCT03639935 – This trial combines Rucaparib (a PARP inhibitor) with Nivolumab (an immune checkpoint inhibitor) in patients with advanced or metastatic biliary tract cancer. The trial is currently in Phase II, and while results are still being collected, the completion is expected in early 2025.
   https://clinicaltrials.gov/ct2/show/NCT03639935
2. NCT04972110 – This trial is looking at the combination of Olaparib (a PARP inhibitor) and Camonsertib (an ATR inhibitor). It’s an early-stage study aimed at patients with DNA repair defects, like those seen in IDH1 mutations. The trial is ongoing, and updates are still being collected.
   https://clinicaltrials.gov/ct2/show/NCT04972110

These studies are particularly interesting as they help us better understand whether combining different therapies, like PARP inhibitors with ICIs or ATR inhibitors, can provide better outcomes for patients with complex cancers like iCCA.

Let me know if you’d like help digging into any specific details or connecting with trial networks here in Australia.

Steve

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